Adjuvant use of the PD-1 inhibitor pembrolizumab achieved a statistically significant and clinically meaningful improvement in disease-free survival in patients with high-risk muscle-invasive urothelial carcinoma vs observation after surgical resection, according to an interim analysis of the phase III AMBASSADOR trial presented at the 2024 ASCO Genitourinary Cancers Symposium.¹ No unexpected safety findings were reported.

At a median follow-up of 22.3 months, disease-free survival was 29 months with pembrolizumab vs 14 months with observation alone (P = .001). However, median overall survival was not statistically significant after a median follow-up of 3 years.

“The trial met its primary efficacy endpoint and is a positive trial,” said lead author Andrea B. Apolo, MD, of the National Cancer Institute. “At the interim analysis, the overall survival endpoint was not met, which may have been due to the high number of patients in the observation arm receiving a checkpoint inhibitor,” she added.

“The result of this study [AMBASSADOR] emphasizes there is a value to adding a checkpoint inhibitor after surgery in those patients who have very high–risk features....”

— Andrea B. Apolo, MD

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Radical surgery with or without neoadjuvant cisplatin-based therapy is the standard of care for patients with muscle-invasive urothelial carcinoma, but many patients cannot tolerate cisplatin-based chemotherapy or are ineligible for it. Additionally, patients treated with neoadjuvant chemotherapy are not recommended to have adjuvant cisplatin-based therapy.

“We conducted the [AMBASSADOR] study to see if there was a benefit to giving an immune checkpoint inhibitor after surgery for those patients who had persistent muscle-invasive disease after neoadjuvant chemotherapy or for those who, for some reason, could not get neoadjuvant chemotherapy,” Dr. Apolo explained.

Study Details

AMBASSADOR is an open-label, randomized, phase III trial evaluating the efficacy and safety of pembrolizumab as an adjuvant treatment in muscle-invasive and locally advanced urothelial carcinoma vs observation. The study included 702 patients with histologically confirmed muscle-invasive urothelial carcinoma of the bladder, upper tract, or urethra who had radical cystectomy, nephrectomy, nephroureterectomy, or ureterectomy after neoadjuvant platinum-based chemotherapy. Patients were then randomly assigned in a 1:1 ratio to receive treatment with either pembrolizumab (n = 354) or observation (n = 348). The co-primary endpoints were disease-free survival and overall survival. Secondary endpoints included disease-free survival and overall survival in subgroups of PD-L1–positive and –negative patients as well as safety.

Patients in the pembrolizumab arm received a mean of 11 treatment cycles. No patient enrolled in the trial is currently receiving study treatment.

At baseline in the pembrolizumab arm, median patient age was 69. The overwhelming majority of patients enrolled in the trial were White (91%), and 76.6% were male. About two-thirds (65.3%) had received neoadjuvant therapy. More than half (57%) had PD-L1–positive disease. These percentages were similar in the observation arm.

Key Outcomes and Safety

The median follow-up was 22.3 months for disease-free survival and 36.9 months for overall survival. Patients treated with pembrolizumab had a median disease-free survival of 29.0 months with pembrolizumab compared with 14.0 months with observation. “The median disease-free survival was more than doubled for patients who received pembrolizumab, and the hazard ratio was 0.69,” Dr. Apolo stated.

All prespecified subgroups had a benefit from pembrolizumab vs observation, with the exception of patients with a primary tumor in the upper tract. “The upper tract subgroup…needs further investigation, and the magnitude of benefit [of pembrolizumab] is unclear [in those patients],” she said.

In patients with PD-L1–positive disease (combined positive score [CPS] of ≥ 10%), median disease-free survival was 32.8 months vs 20.7 months with observation. In patients with PD-L1–negative disease, the median disease-free survival was 22.1 months vs 9.1 months (P = .002).

“Interestingly, it was the patients who were PD-L1–negative who had the most benefit from receiving pembrolizumab, and that was a little surprising to us,” she told listeners.

At the interim analysis, the median overall survival was 50.9 months in the pembrolizumab arm and 55.8 months in the observation arm. Two previous trials testing adjuvant treatment with atezolizumab and nivolumab respectively, in the same patient population showed conflicting results for disease-free survival, leaving the utility of adjuvant checkpoint inhibitor questionable in this setting.^2,3

Median overall survival in PD-L1–positive patients was not reached with pembrolizumab vs 56.1 months with observation. Median overall survival in patients with PD-L1–negative disease was 43.8 months vs 36.7 months, respectively. “PD-L1 positivity using the CPS score was associated with a better prognosis but was not predictive for treatment efficacy. PD-L1 status should not be used to select patients for treatment,” she stated.

Dr. Apolo continued: “The result of this study is really important because it does emphasize there is a value to adding a checkpoint inhibitor after surgery in those patients who have very high–risk features (eg, large tumors, T3 or T4 tumors, persistent muscle-invasive disease after neoadjuvant chemotherapy, and positive lymph nodes).”

Unlike other trials in this setting, the AMBASSADOR trial allowed enrollment of patients with positive surgical margins. “This group of patients also benefited from the addition of pembrolizumab in the adjuvant setting; this was the first adjuvant study that allowed this patient group,” she added.

Regarding safety, no unusual adverse events were reported in patients treated with pembrolizumab. “Pembrolizumab is easier to tolerate than chemotherapy, so the safety profile of pembrolizumab is very well known, because it is already approved in the metastatic setting for bladder cancer,” Dr. Apolo said. “As expected, there were common immune-related side effects, but nothing out of the ordinary.”

Grade 3 or higher adverse events were reported in 48.4% and 31.8% of patients in the pembrolizumab and observation arms, respectively.

“These results support pembrolizumab as a new therapeutic option for patients with muscle-invasive urothelial carcinoma at high risk of recurrence,” Dr. Apolo stated. “Nivolumab is now FDA approved [for this indication], and I think pembrolizumab has shown it is as active as nivolumab in this setting.… They both have similar disease-free survival activity,” she added. 

DISCLOSURE: Dr. Apolo reported no conflicts of interest.

REFERENCES

1. Apolo AB, Ballman KV, Sonpavde GP, et al: AMBASSADOR Alliance A031501: Phase III randomized adjuvant study of pembrolizumab in muscle-invasive and locally advanced urothelial carcinoma vs observation. 2024 ASCO Genitourinary Cancers Symposium. Abstract LBA531. Presented January 26, 2024.

2. Bellmunt J, Hussain M, Gschwend JE, et al: Adjuvant atezolizumab versus observation in muscle-invasive urothelial carcinoma (IMvigor010): A multicentre, open-label, randomised, phase 3 trial. Lancet Oncol 22:525-537, 2021.

3. Bajorin DF, Witjes JA, Gschwend JE, et al: Adjuvant nivolumab versus placebo in muscle-invasive urothelial carcinoma. N Engl J Med 384:2102-2114, 2021.

EXPERT POINT OF VIEW

Invited discussant of the AMBASSADOR trial, Max R. Kates, MD, of Johns Hopkins Medicine, said nivolumab is currently the standard of care in the adjuvant setting for patients with persistent muscle-invasive urothelial cancer, patients with T3 or T4 bladder cancer, or those with lymph node–positive disease, after systemic therapy. Pembrolizumab has not been used in this setting previously, and the findings from the AMBASSADOR trial highlight the potential utility of this agent in high-risk muscle-invasive urothelial cancer.

Max R. Kates, MD

Previous studies of adjuvant immune checkpoint inhibitors as adjuvant therapy for muscle-invasive urothelial cancer have had conflicting results: IMvigor010 of atezolizumab and CheckMate 274 of nivolumab. Dr. Kates said the findings from the AMBASSADOR study validate the findings of CheckMate 274, the first positive trial for an immune checkpoint inhibitor in the adjuvant setting.

“This trial likely tips the scale in providing further evidence that there is a clear, cogent rationale for giving adjuvant therapy in patients with high-risk muscle-invasive bladder cancer,” Dr. Kates concluded. 

DISCLOSURE: Dr. Kates reported financial relationships with Astellas Pharma, Genesis, Biotech Group, Merck, NanOlogy, Pacific Edge, and Photocure.